Enteral nutritional product for patients undergoing radiation therapy and/or chemotherapy

ABSTRACT

An enteral nutritional product has been formulated for persons who are currently undergoing radiation therapy and/or chemotherapy. The nutritional product has a protein system which includes a soy protein hydrolysate. The nutritional product is very low in folic acid, contains β-carotene, and has a ratio of n-6 to n-3 fatty acids that is in the range of about 1.3:1 to 2.5:1.

The present invention relates to an enteral nutritional product forpatients who are currently undergoing chemotherapy and/or radiotherapy.

Radiotherapy and/or chemotherapy are often used, for example, for theeradication of malignant cells present in the body, or for the treatmentof other diseases. When one considers the example of abdominopelviccarcinomas treated with radiotherapy, pelvic radiation cannot killmalignant cells without causing some damage to the surrounding normaltissues. The normal tissue most often affected is the intestinal mucosawhich, because of its rapidly dividing cells, is very radiosensitive.This same phenomenon also holds true for the use of chemotherapy in theeradication of malignant cells located throughout the body, or thetreatment of other diseases, when treatment renders toxic trauma to thegastrointestinal tract. As an example, although chemotherapy iseffective in targeting the malignant cells, or treating other diseases,its use is often associated with significant damage to normalnonmalignant cells, such as those which line the gastrointestinal tract.It is the failure to maintain homeostasis between cell depletion(induction of apoptosis) and cell proliferation (survival of pluripotentcells) with each successive dose of pelvic radiation and/or chemotherapythat results in the clinically observed acute gastrointestinal symptoms.Symptoms of both acute radiation/chemotherapy-induced damage representthe expression of radiation/chemotherapy-induced apoptosis and resultantfunctional changes in the bowel mucosa. Morphological changes as aresult of pelvic radiation-and/or chemotherapy-induced apoptosisinclude, but are not limited to: (1) villi shortening; (2) reduction intotal epithelial surface area; (3) reduction or disappearance of theglycocalyx and (4) loss of pluripotent cells.

Functional changes in the small bowel, induced by pelvic irradiationand/or chemotherapy include: malabsorption of fat, carbohydrate,protein, and bile salts, and clinically presents as diarrhea. Symptomsof nausea, vomiting and anorexia may also be experienced which resultsin a general nutritional wasting which is reversible. If these symptomscontinue, weight loss, dehydration and severe nutrient losses occur.Symptoms of acute radiation/chemotherapy-induced enteritis usually abateshortly after the completion of treatment. The segment of the smallintestine most affected by pelvic radiation is the ileum, and this isdue to its pelvic position which puts it directly into the field of theradiation beam. The sigmoid colon could also be affected by pelvicradiation treatment due to its pelvic position.

The onset of chronic pelvic radiation injury may be delayed for monthsto years. Symptoms include intermittent bowel obstruction, fistulas,ulceration, perforation and generalized malabsorption. In theliterature, there appears to be controversy over the natural history ofchronic radiation-induced injury. Some report that an uneventfulclinical course during and immediately after radiation does not providea guarantee against the later development of malabsorption, obstruction,fistula or other complications. Others report that there appears to beno case of delayed enteropathy without a history of acute enteritis.Currently, there is no predictive test of late bowel damage. Medicalmanagement of late bowel damage is difficult and these latecomplications of radiation therapy can have an adverse effect on thehost's nutrition status. The same scenario holds true for chronicchemotherapy-induced injury to the gastrointestinal tract.

The appropriate oral dietary interventions for clients withradiation/chemotherapy-induced enteritis are not well defined in theliterature. Traditionally, low lactose, low roughage diets have beenemployed and may provide some relief of symptoms. Kouba, "Nutritionalcare of the individual with cancer", Nutrition in Clinical Practice,3:175-182, 1988; Coulston, et al., "Nutrition management of patientswith cancer", Topics in Clinical Nutrition, 12:26-36, 1986. Morerecently the use of elemental diets (chemically defined products thatcontain most nutrients in their simple molecular form) have beendescribed as having an important role in preserving the morphologicalintegrity of the gastrointestinal mucosa during radiation treatment.Bounous, "The use of elemental diets during cancer therapy", AnticancerResearch, 3:299-304, 1983 If this can be confirmed, then acute andchronic radiation/chemotherapy-induced side effects could be minimizedby the addition of an elemental diet throughout the course of pelvicradiation and/or chemotherapy treatment. Furthermore, nutritionalsupport and symptom management may allow patients to more easilywithstand treatment protocols, thus improving tumor control and overallpatient prognosis and well-being.

Various animal models have been used to study the efficacy of elementaldiets to protect against radiation/chemotherapy-induced bowel injury.Mice fed an elemental diet during single dose irradiation ranging from700-1350 cGY were observed to have a better survival and less weightloss than mice eating regular diets. Hugon et al., "Elemental diet inthe management of the intestinal lesions produced by radiation in themouse", Canadian Journal of Surgery 15:18-26, 1972

McArdle et al., "Elemental Diet as Prophylaxis Against RadiationInjury", ARCHIVES OF SURGERY, Vol. 120, September 1985, pages 1026-1033reports that feeding an elemental diet to dogs for three days beforegiving 2,000 rad of radiation afforded significant protection to thesmall intestine from the acute phase of radiation injury. The elementaldiet employed in McArdle et al.'s study was VITAL® from RossLaboratories, Columbus, Ohio, U.S.A. McArdle et al. later reported in"Prophylaxis Against Radiation Injury", ARCHIVES OF SURGERY, Vol. 121,August 1986, pages 879-884, that a study involving human patientssuggested that elemental diet feeding provides prophylaxis against theacute phase of radiation injury in patients undergoing high doses,short-course radiotherapy for invasive bladder cancer and that it is asafe and feasible means of postoperative nutritional support, even inthe presence of a fresh bowel anastomosis. The elemental diet employedin this study was also VITAL®.

A case report, Haddad et al., "Long term nutrition with an elementaldiet following intensive abdominal radiation: Report of a case",Diseases of the Colon and Rectum, 17(3):373-375, 1974, investigated thelong-term use of an elemental diet following intensive abdominalradiation in a woman diagnosed with ovarian cancer. Six weeks afterabdominal radiation treatment with a total central pelvic dose of 4100cGy followed by cGy to the whole pelvis, this woman experiencedabdominal distention, abdominal pain, vomiting and weight loss. She wasadmitted to the hospital for nutritional support via nasogastric tubefeedings. Upon discharge she continued to consume an oral elemental dietwhich was well tolerated. The patient's symptoms resolved and hernutritional status improved and was maintained with the elemental diet.Any attempts made to resume her original diet resulted in the resumptionof her previous symptoms of diarrhea and nausea. The patient remainedasymptomatic on the elemental diet. This case was the first report inwhich a chemically defined elemental diet was used exclusively for thelong-term nutritional support of an adult patient experiencing acuteradiation induced injury. Also, the return of symptoms on cross-over tothe regular diet is compelling.

With this background, clinical trials were undertaken to investigate thepossibility of protection against radiation enteropathy by theprophylactic administration of an elemental diet. A prospective studyreported by Bounous et al., "Dietary protection during radiationtherapy", Strahlentherapie, 149:476-483, 1975, alternatively assignedoncology patients undergoing pelvic or abdominal radiation treatment toreceive either an elemental diet or a normal diet. Clinical outcomevariables were weight change and diarrhea. Serum total protein andalbumin levels were also measured. Results from this study indicatedthat subjects on the elemental diet were able to maintain weight andserum protein levels, whereas those in the control group lost weight andserum protein levels decreased. The elemental diet in the above studyappeared to prevent radiation-induced diarrhea and to exert a favorableeffect on the patients nutritional well-being. Radiation-induceddiarrhea was a symptomatic problem experienced by 6 of the 9 subjects inthe control group compared to only 1 of the 9 subjects in the elementaldiet group. Furthermore, 3 of the 9 subjects in the control grouprequired an interruption of radiation treatment because of anexacerbation of these symptoms. This interruption may ultimately affecttumor control and outcome. More importantly, it was evident that thepatients in the study group were able to tolerate the oraladministration of an elemental diet. It is reasonable to hypothesizefrom these observations that an elemental diet will result in fewerinterruptions of radiation treatment, thus improving tumor control.

A more recent study, McArdle et al., "Prophylaxis against radiationinjury", Archives of Survey, 121:879-884, 1986, investigated the use ofan elemental diet in 20 patients undergoing radiation therapy of 2000cGY over five days, prior to radical cystectomy and ileal conduit forinvasive bladder cancer. These patients were supported for 7 days on anelemental diet either by nasogastric tube feeding or by oraladministration. Initially, the research design called for the randomallocation of patients to an elemental diet or to conventional nutritionmanagement which consisted of either Total Parenteral Nutrition (TPN) ora regular hospital diet. A benefit of the elemental diet was observedearly in the study and it was decided to discontinue other modes ofnutritional support for ethical reasons. Hence, after the fourthelemental diet fed patient, the random allocation of patients wasstopped and all patients were placed on an elemental diet andretrospective controls were used for comparison. The important clinicaloutcome of this study was the biopsy results of the terminal ileum takenat the time of surgery. All elemental diet fed patients showed no damageon histologic section. In contrast, moderate to severe radiation-induceddamage was observed in the three consecutive patients who were not fedan elemental diet prior to radiation treatment.

In addition to the above studies, Bounous et al. have also demonstratedthe beneficial effects of an elemental diet in patients undergoingchemotherapy with 5-fluorouracil (5-FU) Bounous et al., "Elemental dietin the management of the intestinal lesion produced by 5-fluorouracil inman", Canadian Journal of Surgery, 14, 1971, pages 312-324. In thisstudy, twenty-four patients, 17 men and 7 women, with advancedmetastatic carcinoma who were each receiving a standard dose of 5-FU,were randomly assigned to one of two experimental groups. The controlgroup continued to consume the normal hospital diet throughout the nineday course of chemotherapy while the experimental group received anelemental diet as their sole source of nutrition during the same period.Patients in the control group eating a normal hospital diet, experiencedsignificant weight loss and specific lesions of the rectal mucosa whilepatients on the experimental elemental diet had no rectal lesions andmaintained their pretreatment body weight.

The effects of diet upon chemotherapy induced enterocolitis are alsoreported in Shou et al., "Dietary Manipulation of Methotrexate--InducedEnterocolitis", JOURNAL OF PARENTERAL AND EXTERNAL NUTRITION, Vol. 15,No. 3, pages 307-312, 1991. The results of this study suggested thatpatients unable to ingest a regular diet while undergoing chemotherapymay benefit from a diet with polypeptides as a nitrogen source ratherthan an elemental diet. This publication advocates that elemental liquiddiets cause changes in intestinal microflora characterized by asignificantly increased level of Gram-negative bacteria. It is allegedthat translocation of bacteria from the intestinal tract through theepithelial mucosa may cause infections that result at least in part frombacterial overgrowth, and that administration of certain elemental dietsresult in atrophy of the intestinal mucosa, with reduced mucosa villousheight and crypt depth and other nondesirable results. It is importantto note, however, that such detrimental results from an enteral diethave not been reported in any other publications.

As mentioned above, the underlying biological premise for clinicallyobservable radiation-induced enteritis is the expression of programmedcell death (apoptosis) in both villus cells (non-dividing cells) andcrypt cells (dividing pluripotent epithelial cells). The prevention ofexpression of such cell death would hypothetically translate intoreduced clinically apparent enteritis, and may indeed further reduce oreliminate delayed onset enteritis. Moreover, the expectation of thisreduction by an enteral formula may be based on the selection ofingredients which have been prescreened in a relevant tissue culturesystem for their inherent capacity to inhibit apoptosis. This basis,coupled with the above review of the literature, indicate that the useof such an elemental diet during pelvic radiation and/or chemotherapytreatment may have significant benefit to cancer patients undergoingtreatment. Formulas selected by such means may reduce the morphologicaland functional changes in the intestinal mucosa associated with pelvicradiation and/or chemotherapy treatment. As a result, clinical morbiditymay be minimized and nutritional status may be maintained. Furthermore,improvement in nutritional support and symptom control may allowpatients to better withstand treatment protocols, which may subsequentlyimprove tumor control.

In summary, the potential clinical benefits of an elemental diet duringpelvic radiotherapy and/or chemotherapy are:

1. Reduction in radiation/chemotherapy-induced injury to the bowelmucosa (inhibition of apoptosis);

2. Reduction in the incidence and severity of bowel symptoms resultingfrom pelvic radiotherapy and/or chemotherapy;

3. Improved patient tolerance to pelvic radiation and/or chemotherapy;and

4. Assurance of a nutritionally adequate diet during treatment.

The present invention is a ready to feed, liquid enteral nutritionalproduct designed specifically for the cancer patient undergoingradiation therapy and/or chemotherapy. (Prior art elemental diets, suchas Vital® have been marketed in a powdered form.) This product isspecially designed to provide the gastrointestinal tract with a uniqueblend of nutrients which act to prophylactically blocktherapeutically-induced enteritis. This product can be utilized eitheras a nutritional supplement or as a sole source of nutrition and can beadministered either orally or via tube feeding. This product is low infolic acid so as not to interfere with anti-folate chemotherapeutictherapies, is low in overall fat content so as not to promote diarrhea,and contains fermentable soluble fiber to provide essential nutrients tothe large intestine. The specific features of this product include: (a)high caloric and nutrient density (1.3 kcal/mL); (b) a unique proteincombination (SPH, whey, and pea proteins); (c) high omega-3 fatty acids;(d) fermentable soluble fiber; (e) reduced folic acid levels; (f) lowfat; and (g) β-carotene fortification.

Protein is provided in one embodiment of in the nutritional product ofthe present invention by a protein system which comprises, by weight:

(a) about 60% of a soy protein hydrolysate;

(b) about 30% of a whey protein concentrate; and

(c) about 10% of a pea protein isolate.

However, in other embodiments of the present invention, the soyhydrolysate comprises by weight 60% to 90% of the protein system.

The soy protein hydrolyzate which is used as a source of protein in thenutritional product of the present invention may be manufactured using aprocess taught in U.S. Pat. No. 4,100,024, which is incorporated hereinby reference for the purpose of teaching a process for manufacturing asoy protein hydrolysate for use in the nutritional product of thepresent invention. Briefly, this process for the preparation ofpolypeptides from soy protein soluble in aqueous media at phis in therange of 2 to 7 involves: hydrolyzing soy protein with a microbial,alkaline proteinase in a concentration ranging from 4 to 25 Anson unitsper kg of soy protein at a substrate concentration of between 5 and 20%w/w soy protein, at a pH in the range of 7.5 to 8.5, until a degree ofhydrolysis in the range of about 8 to 15% is attained, whereafter theenzyme is inactivated by reduction of pH with a food grade acid, therecovering the supernatant from the precipitate. However, it isunderstood that a soy protein hydrolyzate produced by any other processwhich has the characteristics elaborated upon herein may be used in thepractice of the present invention.

An example of a nutritional product containing such a soy proteinhydrolysate is taught in U.S. Pat. No. 4,959,350, but this prior artnutritional product has a pH of lower than 4.5 (as compared to a pH of6.3 to 6.6 in the product of the present invention) and has anosmolality of below about 350 mosm/kg water (as compared to about 600mosm/kg water in the nutritional product of the present invention). Thisprior art nutritional product may be further distinguished from thenutritional product of the present invention by the fat composition,fiber content, and vitamin and mineral profiles of the product of thepresent invention.

The nutritional product of the present invention has been manufacturedusing soy protein hydrolysate obtained from NOVO Industri A/S,Bagsvaerd, Denmark, manufactured according to the above describedprocess. The properties of a soy protein hydrolysate which is suitablefor use in the practice of the present invention have been determined byactual analysis of samples from several lots of soy protein hydrolysateobtained from NOVO Industri and/or specifications selected in accordancewith desired properties.

It is believed to be very important that the soy protein hydrolysateused in the practice of the invention comprise, by weight, not less than76%, preferably not less than 80% protein, not more than 1% fat, and notmore than 5.5%, preferably not more than 4.8% ash. It is also believedto be very important that a 5% slurry (by weight) of the soy proteinhydrolysate in water has a pH in the range of about 4.2 to 4.3, but inany instance less than 4.5. It is believed to be important that thedegree of hydrolysis of the soy protein hydrolysate (AN/TN×100) be inthe range of about 14 to 17 and most preferably about 16.

The amino acid profile of the soy protein hydrolysate that has been usedin the practice of the present invention is presented in Table 1, andthe mineral profile is presented in Table 2. The molecular weightprofile is presented in Table 3 for soy protein hydrolysate (SPH) havingabout a 16% degree of hydrolysis with the approximate molecular weightpartition determined by size exclusion chromatography of samples from 4lots of SPH. The molecular weight profile of the soy protein hydrolysateis believed to be very important because particles sizes are related totheir physical activity and product functionality. That is to say, forthe SPH used in the nutritional product of the present invention themolecular weight profile indicates a large peptide content and a smallfree amino acid content of less than 1%. The mineral profile of the soyprotein hydrolysate is believed to be very important because it suppliesmost of the trace and ultratrace minerals in the nutritional product.

                  TABLE 1                                                         ______________________________________                                        AMINO ACID PROFILE OF SOY                                                     PROTEIN HYDROLYSATE (g/100 gm)                                                ______________________________________                                        Aspartic acid    9.8-10.4                                                     Threonine       2.9-3.2                                                       Serine          3.7-4.4                                                       Glutamic Acid   17.0-18.1                                                     Proline         4.4-4.9                                                       Glycine         3.2-3.3                                                       Alanine         3.0-3.2                                                       Valine          2.9-3.6                                                       Methionine      0.9-1.1                                                       Isoleucine      3.0-3.7                                                       Leucine         5.1-5.3                                                       Tyrosine        2.7-2.9                                                       Phenyl alanine  3.3-3.5                                                       Histidine       2.0-2.2                                                       Lysine          5.5-5.8                                                       Arginine        6.3-6.7                                                       Tryptophan      0.3-0.7                                                       Cystine         1.3-1.4                                                       ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        MINERAL PROFILE OF SOY PROTEIN HYDROLYSATE                                                  Preferred                                                                             Most Preferred                                                        Range   Range                                                   ______________________________________                                        Calcium, mg/100 g                                                                             170-350   170-260                                             Sodium, mg/100 g                                                                              370-650   370-520                                             Potassium, mg/100 g                                                                           180-600   180-470                                             Magnesium, mg/100 g                                                                           270-550   270-400                                             Phosphorus, mg/100 g                                                                           900-1500  900-1200                                           Chloride, mg/100 g                                                                            1400-2500 1400-2250                                           Iron, mg/100 g  13-25     13-20                                               Zinc, mg/100 g  3-6       3-6                                                 Manganese, mg/100 g                                                                           4-8       5-7                                                 Copper, mg/100 g                                                                              0.5-1.5   0.5-1.0                                             Vanadium, ppm   trace-15 .sup.                                                                           8-12                                               Selenium, ppb   trace-350.sup.                                                                          150-300                                             Chromium, ppm   trace-2.9 1.5-2.3                                             Molybdenum, ppm trace-3.7 2-3                                                 ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        MOLECULAR WEIGHT PARTITION FOR SPH                                            (AS DETERMINED BY SIZE EXCLUSION CHROMA-                                      TOGRAPHY OF SAMPLES FROM FOUR DIFFERENT                                       LOTS OF SPH)                                                                            % of Particles With This Molecular Wt.                                                     Std.                                                   Molecular Wt.                                                                             Average    Deviation Range                                        ______________________________________                                        >5000       3.3        1.96      1.70-5.96                                    2000-5000   25.8       5.42      19.50-30.75                                  1500-2000   20.5       7.41      13.10-27.50                                  1200-1500   12.5       0.92      11.80-13.80                                  1000-1200   8.2        0.83      7.30-9.00                                     500-1000   19.5       3.02      16.80-23.80                                  <500        10.2       6.03       5.30-19.00                                  ______________________________________                                    

It was discovered that the soy protein hydrolyzate used in thenutritional product of the present invention does not yield a shelfstable product in the absence of intact protein. Once a protein ishydrolyzed, it loses its primary and secondary structure andconsequently some of its functionality, including emulsifyingproperties. Therefore, it does not have surfactant properties and isunable to stabilize the formulation resulting in phase separation.Various approaches were investigated to attempt to stabilize a liquidproduct containing this particular soy protein hydrolyzate. Threedifferent emulsifiers, and combinations thereof, were evaluated, but themost effective emulsifier is Panodan® which is distributed by GRINSTEDof Danisco, Denmark. Panodan® is diacetyl tartaric acid esters ofmono-diglycerides and is an anionic surfactant with a very hydrophiliccomponent attached. Panodan® is generally regarded as safe (GRAS) foruse in nutritional products for human consumption. Panodan® works byimparting a negative charge to the fat globules, thus, causing them toelectrostatically repel each other so that no flocculation orcoalescence occurs. The soy protein hydrolysate could stay in anemulsion for about two weeks with Panodan®, and no other protein sourcepresent. It is, however, believed that sodium stearolyl lactylate couldalso be used as an emulsifier, but this emulsifier has not yet beenclassified as GRAS by the U.S. Food and Drug Administration. It isbelieved that a product in accordance with the present invention maybemanufactured without an emulsifier if the content of intact protein isgreat enough.

The sources of intact protein selected for use in the product of thepresent invention are pea protein isolate and whey protein concentrate.One of the advantages of using pea protein and whey protein is that ithelps to alleviate the bitter taste of the product. Caution must betaken not to use too much pea protein or the viscosity of the productmay be too high. It is to be understood that the component(s) of theprotein system of a nutritional product of the present inventioncomprising intact protein could comprise any suitable source of intactprotein, such as sodium caseinate, whether in place of or in addition tothe pea protein and whey protein used in the preferred embodiment.

An important feature of the nutritional product of the present inventionis the inclusion of pea protein isolate as a source of protein. Producthas been manufactured using PISANE® PEA PROTEIN ISOLATE distributed byCosucra SA of Momalle, Belgium. This commercially available pea proteinisolate is a cream colored powder of particles having sizes of smallerthan about 150 microns. Per the distributor's sales literature on a dryweight basis the pea protein isolate is: a minimum of 88% protein, amaximum of 0.2% fat, about 5% ash, and the pH of a 10% aqueous solutionof the protein isolate is about 7.5. Per the distributor's salesliterature functional properties of the pea protein isolate are: 60%minimum solubility at pH 7, 15% minimum solubility at pH 4.5, and 90%minimum emulsion stability (0/W =40/60, 1% PISANE®, pH 3 to 7). Table 4presents the average amino acids content of the pea protein isolate perthe distributor's sales literature.

                  TABLE 4                                                         ______________________________________                                        AMINO ACIDS CONTENT OF PEA PROTEIN ISOLATE                                    (g/100 gm protein)                                                            ______________________________________                                               Glycine  4.3                                                                  Alanine  20.7                                                                 Valine   3.7                                                                  Leucine  7.7                                                                  Isoleucine                                                                             3.1                                                                  Serine   5.2                                                                  Threonine                                                                              3.8                                                                  Tyrosine 3.5                                                                  Aspartic acid                                                                          11.8                                                                 Phenylalanine                                                                          5.0                                                                  Tryptophan                                                                             1.0                                                                  Proline  4.4                                                                  Methionine                                                                             1.0                                                                  Cysteine 1.4                                                                  Lysine   7.5                                                                  Histidine                                                                              2.2                                                                  Arginine 7.7                                                                  Glutamic acid                                                                          20.7                                                          ______________________________________                                    

The Bill of Materials for manufacturing a 1,000 pound batch of anutritional product in accordance with the present invention ispresented in Table 5. It is to be understood that this Bill of Materialsis only an example for one flavor that has been manufactured and thatfunctionally equivalent ingredients may be substituted into the Bill ofMaterials without deviating from the scope of the invention.

                  TABLE 5                                                         ______________________________________                                        BILL OF MATERIALS                                                                               AMOUNT 454 Kg                                               INGREDIENT        (1,000 LB) BATCH                                            ______________________________________                                        Medium Chain Triglycerides                                                                      1.785   kg     (3.932 lbs)                                  (MCT) Oil                                                                     Canola Oil        5.081   kg     (12.779                                                                              lbs)                                  Panodan ® (emulsifier)                                                                      445.880 gms                                                 Oil Soluble Vitamin Premix:                                                                     24.140  gms                                                 Vitamin A         1.683   gms                                                 Vitamin D         0.159   gms                                                 Vitamin E         17.319  gms                                                 Vitamin K         0.033   gms                                                 Vitamin A         0.382   gms                                                 β-Carotene   8.935   gms                                                 Iota Carrageenan  68.040  gms                                                 Gum Arabic        3.822   kg     (8.418 lbs)                                  Fish Oil          0.892   kg     (1.966 lbs)                                  Water             315.899 kg     (694.970                                                                             lbs)                                  Whey Protein Concentrate                                                                        11.670  kg     (25.770                                                                              lbs)                                  Sodium Citrate    1.724   kg     (3.797 lbs)                                  Magnesium Phosphate*                                                                            527.970 gms                                                 Calcium Carbonate 465.470 gms                                                 Calcium Phosphate*                                                                              447.060 gm                                                  Maltrin ® 040 (maltodextrin)                                                                71.491  kg     (157.470                                                                             lbs)                                  Sucrose           11.986  kg     (26.400                                                                              lbs)                                  Soy Protein Hydrolysate                                                                         19.931  kg     (43.900                                                                              lbs)                                  Potassium Hydroxide 45%                                                                         3.094   kg     (6.806 lbs)                                  Pea Protein Isolate                                                                             3.234   kg     (7.120 lbs)                                  Zinc Sulfate      8.628   gms                                                 Copper Sulfate    1.717   gms                                                 Sodium Selenate   0.039   gms                                                 Ascorbic Acid     412.364 gms                                                 Choline Chloride  41.667  gms                                                 Carnitine         35.000  gms                                                 Taurine           49.484  gms                                                 Niacinamide       7.635   gms                                                 d-Ca Calcium Pantothenate                                                                       4.885   gms                                                 Folic Acid        0.064   gms                                                 Thiamine HCl      1.186   gms                                                 Riboflavin        1.010   gms                                                 Pyridoxine HCl    1.228   gms                                                 Cyanocobalamin    0.003   gms                                                 Biotin            0.153   gms                                                 Artificial Vanilla                                                                              1.135   kg     (2.500 lbs)                                  Natural and Artificial Vanilla                                                                  0.909   kg     (2.000 lbs)                                  ______________________________________                                         *Phosphorus content may need to be adjusted i view of phytate content of      the SPH.                                                                 

The nutritional product of the present invention may be manufacturedusing the ingredients from the above Bill of Materials by: (a) preparingseveral slurries/solutions which are then combined together; (b) heatprocessing the resultant blend; (c) adding vitamins, minerals andflavorings; and (d) packaging and sterilizing the resultant product.

An oil blend is prepared by the following procedure. The medium chaintriglycerides and canola oil are placed in a vessel and while beingcontinuously agitated are heated to a temperature in the range of about60°-65° (140°-150° F). The product has been manufactured usingfractionated coconut oil as the source of MCT, but any other suitablesource of MCT may be used. Add the Panodan® (an emulsifier) to theresultant oil blend and allow it to dissolve therein before adding theremaining ingredients. Panodan distributed by Grinsted of Danisco,Denmark, (which also has a distributor located in Kansas, U.S.A.) is adiacetyl tartaric acid ester of mono-diglycerides, made from ediblerefried vegetable fat. Add the oil soluble vitamin premix, vitamin A,and β-carotene to the oil blend. Combine the iota carrageenan with thegum arabic, and add this mixture to the oil blend. Cool the oil blend toa temperature in the range of about 43°-49° C. (110°-120° F). Add thefish oil to the oil blend, and maintain the oil blend at a temperatureof about 43°-49° C. (110°-120° F.) under constant agitation until theoil blend is combined with other ingredients. The product has beenmanufactured using marine oil made from tuna and sardine meal,distributed by Mochida International of Shinjuku-ku, Tokyo, Japan, butis produced and packaged by the Sambu-gun, Chiba plant of the KyowaTechnos Co., Ltd.

A protein-in-water slurry is prepared by the following procedure. About95.79 kg (210.74 pounds) of water is placed in a vessel and heated to atemperature in the range of about 54°-60° C. (130°-140° F.). It isbelieved to be critical that the temperature of the water does notexceed 60° C. (140° F.) during this procedure. Add the pea proteinisolate and then the whey protein concentrate to the water, and maintainthe resultant protein-in-water slurry under agitation at a temperatureof about 54° C. (130° F.) until this slurry is combined with otheringredients. The resultant slurry is about 13.5% total solids.

A carbohydrate slurry is prepared by the following procedure. About30.41 kg (286.9 pounds) of water is placed in a vessel and heated to atemperature in the range of about 68°-74° C. (155°-165° F.). Dissolvethe sodium citrate, magnesium phosphate, calcium carbonate, and calciumphosphate in the water. To the resultant solution add the Maltrin® 040(distributed by Grain Processing Company of Muscatine, Iowa, U.S.A.) andagitate the solution until the Maltrin®040 is dissolved therein.Maltrin® 040 is a maltodextrin, or corn syrup solid. The number 40refers to the dextrose equivalent of the ingredient (4 to 7) and wasselected to minimize the effect of this ingredient on the osmolality ofthe nutritional product. To the resultant solution add the sucrose andthe soy protein hydrolysate. The resultant slurry should have a pH ofabout 4.3. Add 3.09 kg (6.806 lbs) of 45% potassium hydroxide to theslurry in an amount sufficient to adjust the pH of the slurry to be inthe range of about 6.3-6.5. (If necessary the amount of 45% potassiumhydroxide may exceed the amount specified). The slurry is maintained ata temperature in the range of about 54°-60° C. (130°-140° F.) underagitation until the slurry is combined with other ingredients. Theresultant slurry is about 45% of total solids prior to the addition ofthe potassium hydroxide.

The oil blend, carbohydrate slurry, and first and secondprotein-in-water slurries are all combined together. The resultant finalblend is then heat processed by the following procedure:

(a) The final blend is preheated to a temperature in the range of about68°-74° C. (155°-165° F.).

(b) The final blend is de-aerated at 13-15 psi.

(c) The final blend is emulsified at 900-1100 psig.

(d) The final blend is heated to a temperature in the range of about98°-106° C. (208°-222° F.) using a plate heater.

(e) The final blend is then heated to a ultra-high temperature in therange of about 146°-147° C. (294°-297° F.), and is held at thistemperature for 5 seconds.

(f) The final blend is then flash cooled to a temperature in the rangeof about 98°-106° C. (208°-222° F.), then plate cooled to a temperaturein the 71°-79° C. (160°-175° F.).

(g) The final blend is homogenized at 3900-4100/400-600 psig.

(h) The final blend is held at a temperature in the range of about74°-85° C. (165°-185° F.) for 16 seconds.

(i) The final blend is then cooled to a temperature in the range ofabout 1°-7° C. (34°-45° F.), and held at this temperature until theproduct is sealed in containers (preferably within 48 hours).

An ultra trace mineral solution is prepared by the following procedure.About 93.89 gm (0.207 pounds) of water are placed in a vessel and heatedto a temperature in the range of about 66°-71° C. (150°-160° F.). Thezinc sulfate, copper sulfate and sodium selenate are then added to thewater and the solution is agitated until these ingredients dissolve inthe water. The resultant solution is about 10% total solids. Theresultant solution is then added to the final blend.

A water soluble vitamin solution is then prepared by the followingprocedure. About 2.89 kg (6.366 pounds) of room temperature water isplaced in a vessel. The ascorbic acid, 45% potassium hydroxide (284.4 gm(0.627 lbs), choline chloride, carnitine, and taurine are added to thewater with agitation. To the resultant solution the following vitaminsare added: niacinamide, d-calcium pantothenate, folic acid, thiamineHCl, riboflavin, pyridoxine HCl, cyancobalamin, and biotin. Theresultant solution is about 20% total solids. The resultant solution isthen added to the final blend. It is understood that in large scaleproduction it would be preferable to have the water soluble vitaminsprovided in a premix.

A flavor solution is then prepared by the following procedure. About86.71 kg (190.757 pounds) of room temperature water is placed in avessel. The vanilla and MAG are dissolved in the water. The resultantsolution is about 5% of total solids. The flavor solution is then addedto the final blend. The resultant final blend is about 29% total solids.

The final blend is then placed in suitable containers, such as 8 ouncecans, sealed with a suitable closure, and subjected to terminalsterilization.

The nutrient profile of a nutritional product in accordance with theinvention is presented in Table 6. The amino acid profile of the newnutritional product is presented in Table 7, and the fatty acid profileof the new nutritional product is presented in Table 8.

                                      TABLE 6                                     __________________________________________________________________________    NUTRIENT PROFILE OF PRODUCT                                                                    TARGET ACCEPTABLE RANGE                                                       (per 8 (per 8                                                                 fluid oz.)                                                                           fluid oz. can)                                                                       per liter                                      __________________________________________________________________________    Total Solids     75.64  73.3-78.0                                                                            309.7-329.6                                    Protein, g       15.83  15.4-16.3                                                                            65.1-68.9                                      60% Soy Protein Hydrolyzate                                                   30% Whey Protein Concentrate                                                  10% Pea Protein Isolate                                                       Fat, g           5.43   5.2-6.1                                                                              22.0-26.0                                      65% Canola Oil                                                                20% MCT Oil                                                                   10% Fish Oil                                                                  5% Panodan (emulsifier)                                                       Carbohydrate, g  46.80  44.9-49.6                                                                            189.7-209.6                                    85% Maltrin ® 040                                                         15% Sucrose                                                                   Fiber (Gum Arabic), g                                                                          1.90   1.4-2.5                                                                               5.9-10.5                                      Water Soluble Vitamins                                                        Vitamin C, mg    189    151-236                                                                               640-1000                                      Folic Acid, mcg  36.6   33.0-42.5                                                                            139.4-179.6                                    Thiamine, mg     0.66   0.59-0.90                                                                            2.49-3.80                                      Riboflavin, mg   0.57   0.49-0.71                                                                            2.07-3.00                                      Pyridoxine, mg   0.6    0.4-0.7                                                                              2.0-2.8                                        Cyancobalamin, mcg                                                                             1.73   1.55-2.36                                                                            6.6-9.5                                        Niacin, mg       4.3    3.7-5.9                                                                              15.6-24.9                                      Choline, mg      34.3   30.7-37.8                                                                            129.7-159.7                                    Biotin, mcg      87.5   77.9-96.9                                                                            329.1-409.4                                    Pantothenic Acid, mg                                                                           2.4    2.1-4.7                                                                               9.0-17.5                                      Oil Soluble Vitamins                                                          Vitamin A, IU    1198   1063-1654                                                                            4491-6988                                      Vitamin D, IU    91      82-100                                                                              346-422                                        Vitamin E, IU    9.9     8.5-10.9                                                                            35.9-46.0                                      Vitamin K, mcg   18.9   16.5-24.6                                                                             69.7-104.0                                    β-Carotene, mcg                                                                           945     709-1418                                                                            2995-5948                                      Minerals                                                                      Calcium, mg      234    195-273                                                                               825-1155                                      Sodium, mg       320    283-354                                                                              1196-1496                                      Potassium, mg    475    449-567                                                                              1897-2396                                      Magnesium, mg    100     89-118                                                                              376-498                                        Phosphorus, mg   296    260-338                                                                              1100-1430                                      Chloride, mg     350    330-378                                                                              1394-1597                                      Molybdenum, mcg  63.8    16-106                                                                               67-448                                        Iodine, mcg      21.3   18.9-37.2                                                                             79.8-157.5                                    Manganese, mcg   0.9    0.7-1.2                                                                              3.0-5.1                                        Copper, mg       0.5    0.2-0.7                                                                              0.8-3.0                                        Zinc, mg         2.4    1.1-3.5                                                                               4.6-14.8                                      Iron, mg         3.5    2.8-3.5                                                                              11.8-14.8                                      Selenium, mcg    17.7   11.8-23.6                                                                            49.9-99.7                                      Chromium, mcg    33.1   11.8-47.3                                                                             49.9-199.8                                    Carnitine, mg    20.1   17.7-26.0                                                                             74.8-109.8                                    Taurine, mg      28.4   14.1-30.7                                                                             59.6-129.7                                    __________________________________________________________________________

                  TABLE 7                                                         ______________________________________                                        AMINO ACID PROFILE OF PRODUCT                                                                 g/100 g                                                       AMINO ACID      sample                                                        ______________________________________                                        Aspartic Acid   0.753                                                         *Threonine      0.307                                                         Serine          0.339                                                         Glutamic Acid   1.231                                                         Proline         0.351                                                         Glycine         0.221                                                         Alanine         0.275                                                         *Valine         0.274                                                         *Methionine     0.092                                                         *Isoleucine     0.290                                                         *Leucine        0.503                                                         Tyrosine        0.205                                                         *Phenylalanine  0.276                                                         Histidine       0.153                                                         *Lysine         0.480                                                         Arginine        0.391                                                         *Tryptophan     0.062                                                         Cystine         0.105                                                         TOTAL           6.307                                                         ______________________________________                                         *Essential amino acid                                                    

                  TABLE 8                                                         ______________________________________                                        FATTY ACID PROFILE OF PRODUCT                                                                   % of TOTAL                                                  FATTY ACID        FATTY ACIDS                                                 ______________________________________                                        Caprylic (8:0)    12.5                                                        Capric (10:0)     8.9                                                         Lauric (12:0)     0.4                                                         Myristic (14:0)   1.1                                                         Palimic (16:0)    5.3                                                         Palmitoleic (16:1n7)                                                                            1.0                                                         Stearic (18:0)    3.8                                                         Oleic (18:1n9)    39.1                                                        Linoleic (18:2n6) 14.2                                                        Alpha-Linolenic (18:3n3)                                                                        6.0                                                         Stearidonic (18:4n3)                                                                            0.4                                                         Arachidic (20:0)  0.4                                                         Eicosenoic (20:1n9)                                                                             1.0                                                         Arachidonic (20:4n6)                                                                            0.2                                                         Eicosapentaenoic (20:5n3)                                                                       2.9                                                         Erucic (22:1n9)   0.4                                                         Docsapentaenoic (22:5n3)                                                                        0.3                                                         Docosahexaenoic (22:6n3)                                                                        1.3                                                         Others            0.6                                                         ______________________________________                                    

The enteral nutritional product of the present invention ischaracterized by the ratio, by weight, of the sum of the n-6 fatty acidsto the sum of the n-3 fatty acids being in the range of about 1.3:1 to2.5:1.

The nutritional product of the present invention is low in folic acidcontent because folic acid competes with some of the drugs used incancer therapy for dihydrofolate reductase enzyme and methyl transfer.

The nutritional product of the present invention contains β-carotene,carnitine and taurine. β-carotene is a carotenoid compound that has provitamin A activity. However, unlike vitamin A, β-carotene is notassociated with toxicity and, therefore, may be used as a source ofretinol equivalents in the diet without inducing toxicity concerns.Vitamin A has been shown to reverse some of the immunosuppressionassociated with thermal injury and radiation injury. Favorable effectson the immune system also have been observed with β-carotenesupplementation.

Although carnitine and taurine are present in low but adequate levels ina normal diet, these conditionally essential nutrients may becomelimiting under some circumstances. Carnitine deficiency has beenobserved in sepsis and trauma and during long-term enteral nutritionsupport. Evidence of taurine depletion has been demonstrated aftersurgical trauma and a decline in serum taurine concentrations duringmetabolic stress suggests that taurine supplementation is needed in thatstate. In humans intensive cytoxic chemotherapy is known to reducetaurine levels.

As used herein and in the claims "dietary fiber" and/or "total dietaryfiber" is understood to mean plant material that is undigested by humanalimentary enzymes. Dietary fiber is known to be beneficial inregulating bowel function in diarrhea. Inclusion of dietary fiber in thediet also stimulates the renewal of intestinal epithelial cells andmucosal growth. The nutritional product of the present inventioncontains fermentable soluble dietary fiber in the form of gum arabic.

The enteral nutritional product of the present invention is formulatedto be used as a sole source of nutrition over a relatively short periodof time: for example, starting a few days before this initiation ofchemotherapy and/or radiation therapy, during the therapy period, andstopping two or three days after the completion of the therapy period.Feeding of this new enteral nutritional product over a longer period oftime will result in a decrease in the beneficial response to thenutritional product. Preferably, during periods between theadministration of chemotherapy and/or radiation therapy the patient willconsume a normal healthy diet. If it is necessary to supplement thepatient's diet during periods between the administration of chemotherapyand/or radiation therapy a nutritional supplement of the type disclosedin commonly assigned U.S. Patent application Ser. No. 08/069,067 filedMay 28, 1993 can be consumed by the patient.

We claim:
 1. A liquid enternal nutritional product comprising:(a) a soyprotein hydrolysate having a molecular weight partition, as determinedby size exclusion chromatography, wherein 30-60% of the particles have amolecular weight in the range of 1,500-5,000 Daltons, and the soyprotein hydrolysate provides by weight 60% to 90% of the protein in thenutritional product; (b) a second source of protein which comprises asource of intact protein in a quantity sufficient to yield a stableemulsification of the soy protein hydrolysate and the intact protein inthe nutritional product, the intact protein comprising by weight atleast 10% of the protein in the nutritional product, said second sourceof protein comprising pea protein; (c) a source of fat characterized bythe ratio, by weight, of the sum of the n-6 fatty acids to the sum ofthe n-3 fatty acids being in the range of about 1.3:1 to 2.5:1; saidnutritional product being terminally sterilized and having a pH of about6.3-6.6.
 2. An enteral nutritional product according to claim 1 whereinthe source of intact protein is a combination of pea protein and wheyprotein.
 3. An enteral nutritional product according to claim 2 furthercomprising gum arabic.
 4. An enteral nutritional product according toclaim 1 further comprising a source of dietary fiber.
 5. An enteralnutritional product according to claim 1 having a fat content of 22 to26 g of fat per liter.
 6. An enteral nutritional product according toclaim 1 further comprising about 2,995 to 5,948 mcg per liter ofβ-carotene.
 7. A liquid enteral nutritional product comprising:(a) afirst source of protein comprising a soy protein hydrolysate having adegree of hydrolysis in the range of about 14 to 17% and a molecularweight partition, as determined by size exclusion chromatography,wherein 30-60% of the particles have a molecular weight in the range of1,500-5,000 Daltons, and the soy protein hydrolysate provides by weight60% to 90% of the protein in the nutritional product; (b) a secondsource of protein comprising a combination of intact pea protein andintact whey protein, the intact proteins comprising in combination byweight at least 10% of the protein in the nutritional product; and (c) asource of fat characterized by the ratio, by weight, of the sum of then-6 fatty acids to the sum of the n-3 fatty acids being in the range ofabout 1.3:1 to 2.5:1; said nutritional product being terminallysterilized and having a pH of about 6.3-6.6.
 8. An enteral nutritionalproduct according to claim 7 further comprising about 2,995 to 5,948 mcgper liter of β-carotene.
 9. An enteral nutritional product according toclaim 8 further comprising gum arabic.
 10. An enteral nutritionalproduct according to claim 7 further comprising a source of dietaryfiber.
 11. An enteral nutritional product according to claim 10 having afat content of 22 to 26 g of fat per liter.
 12. An enteral nutritionalproduct according to claim 8 further comprising gum arabic.
 13. Anenteral nutritional product according to claim 12 having a fat contentof 22 to 26 g of fat per liter.
 14. An enteral nutritional productaccording to claim 7 having a fat content of 22 to 26 g of fat perliter.
 15. An enteral nutritional product according to claim 7 having aprotein source comprising by weight about 60% of said soy proteinhydrolysate, about 30% of said whey protein, and about 10% of said peaprotein.
 16. A liquid enteral nutritional product comprising:(a) a firstsource of protein comprising a soy protein hydrolysate having a degreeof hydrolysis in the range of about 14 to 17 % and a molecular weightpartition, as determined by size exclusion chromatography, wherein 30 to60% of the particles have a molecular weight in the range of 1,500-5,000Daltons, and said soy protein hydrolysate provides, by weight about 60%of the protein in said nutritional product; (b) a second source ofprotein comprising intact whey protein concentrate, said whey proteinconcentrate comprising, by weight, about 30% of the protein in saidnutritional product; (c) a third source of protein comprising intact peaprotein isolate, said pea protein isolate comprising, by weight, about10% of the protein in said nutritional product; (d) a source of diacetylacid esters of mono-diglycerides; (e) a fat blend comprising fish oiland at least one other source of fat, said fat blend characterized bythe ratio, by weight, of the sum of the n-6 fatty acids to the sum ofthe n-3 fatty acids being in the range of about 1.3:1 to 2.5:1; saidnutritional product being terminally sterilized and having a pH of about6.3-6.6.
 17. An enteral nutritional product according to claim 16further comprising gum arabic.
 18. An enteral nutritional productaccording to claim 16 further comprising about 2,995 to 5,948 mcg perliter of β-carotene.
 19. An enteral nutritional product according toclaim 16 having a fat content of 22 to 26 g of fat per liter.